WO2008056452A1

WO2008056452A1 - Utilization of rare sugar for slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis

Info

Publication number: WO2008056452A1
Application number: PCT/JP2007/056165
Authority: WO
Inventors: Masaaki Tokuda; Toshifumi Itano; Ken Izumori; Osamu Miyamoto
Original assignee: National University Corporation Kagawa University; Rare Sugar Production Technical Research Laboratories, Llc.
Priority date: 2006-11-09
Filing date: 2007-03-26
Publication date: 2008-05-15
Also published as: JPWO2008056452A1; JP5317055B2

Abstract

[PROBLEMS] To provide a drug or a food for specified health uses aiming at slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis. [MEANS FOR SOLVING PROBLEMS] An agent containing D-allose as the active ingredient and aiming at slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis. A composition in the form of a food, a drink or a drug which contains the agent for slowing the onset or progress as described above. The above-described composition wherein the daily dose of D-allose is from 0.5 to 50 g. A food or a drink containing D-allose as the active ingredient which is indicated as being used for slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis. A method of slowing the onset or progress of mobility impairment relating to amyotrophic lateral sclerosis in a human subject which comprises administering or feeding D-allose in an efficacious amount to the subject. A method of treating a human subject diagnosed as suffering from amyotrophic lateral sclerosis which comprises administering or feeding to the subject D-allose in an efficacious amount for slowing the progress of mobility impairment.

Description

Use of rare sugars to delay the onset or progression of movement disorders associated with amyotrophic lateral sclerosis

Technical field

[0001] The present invention relates to a pharmaceutical product or a food for specified health use, which contains D-allose as an active ingredient and delays the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis. The present invention also relates to a method of delaying the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis in a subject by administering to the subject a therapeutically effective amount of D-allose.

Background art

[0002] Amyotrophic lateral sclerosis (ALS) mainly develops from hand or foot weakness or bulbar symptom after middle age, and weakness of the extremities and muscle atrophy progress over a period of several years. It is a neurodegenerative disease that leads to death due to muscle paralysis. In ALS, upper and lower motor neurons are selectively impaired, usually without sensory impairment or dementia. Pathologically, anterior spinal horn and anterior root atrophy, degeneration and loss of motor neurons in the spinal cord and brainstem motor nucleus, and loss of large pyramidal cells in the motor cortex are observed. To date, hypotheses such as (1) oxidative stress caused by free radicals, (2) glutamate neurotoxicity, and (3) impaired axonal transport have been estimated as the mechanism of motor neuron degeneration. The pathophysiology has not been elucidated. Also, the mechanism by which exercise-euron is selectively impaired is unclear.

[0003] Most people with ALS are sporadic, but 5-10% are familial and many are known to have an autosomal dominant form of inheritance, called familial ALS (FALS). ing. In 1991, it became clear that some FALS families were linked to the long arm of chromosome 21, and in 1993, the copper 'zinc superoxide dismutase (Cu / Zn SOD) gene was the causative gene. Identified. The Cu / Zn SOD gene is 11.5 kb in length and consists of 5 etasons. Cu / ZnSOD protein is a dimer of about 32 kDa, consisting of two 153 amino acids and a protein of about 16 kDa. Each component unit contains one copper ion and one zinc ion. It is an enzyme that disproportionates superoxide, one of the free radicals, and mediates the reaction with hydrogen peroxide.

[0004] Cu / Zn SOD gene abnormalities have been observed in about 20% of FALS patients, and about 60 gene mutations have been reported to date, most of which are point mutations. Differences in age of onset and duration of illness vary depending on the type of mutation. From the previous reports, for example, the 46th amino acid strength of histidine from Cu / Zn SOD reported in Japanese families was arginine. Individuals with FALS who have a mutation to H46R (H46R mutation) are characterized by an extremely long duration of 16.8 years on average. Initially, due to the nature of Cu / Zn SOD as a free radical scavenger, it was thought that the pathogenesis was caused by degeneration of nerve cells by increasing intracellular free radicals due to a decrease in enzyme activity due to gene mutation. However, the age of onset and the degree of symptom progression do not correlate with the Cu / Zn SOD enzyme activity of the affected individuals, and transgeneic mice (Tg mice) introduced with normal human Cu / Zn SOD genes have clinical symptoms. However, Tg mice introduced with mutant Cu / Zn SOD develop ALS-like symptoms of limb muscle atrophy and muscle weakness, and conversely, Cu / Zn SOD knockout mice do not show ALS-like symptoms. Currently, the newly acquired neurotoxicity of the mutated Cu / Zn SOD protein is considered to be a pathological condition.

[0005] Currently, the mechanism of mutated Cu / Zn SOD protein is assumed as the mechanism of degeneration of nerves. (1) Mutant Cu / Zn SOD force It changes structurally or releases copper. The enzyme activity that catalyzes the production of hydroxyl radicals causes cytotoxicity. (2) Mutant Cu / Zn SOD promotes the production of radical peroxynitrite and damages cells. (3) Mutant Cu / Zn SOD aggregates, which damages cells. So far, three strains of Tg mice introduced with the human mutant Cu / Zn SOD gene have been created, and these mice are known to develop ALS-like symptoms, although the changes in symptoms and pathology are different. Yes. As described above, there are various hypotheses regarding the pathogenesis of ALS. The only established primary pathogenesis is the mutation of the Cu / Zn SOD gene.

[0006] Tohoku University Department of Neurology searched for the Cu / Zn SOD gene in FALS patients and reported a new mutation Among them, the 46th histidine is at the active center to which the copper ion of Cu / Zn SOD binds , Cu / Zn SOD enzyme activity is mostly present when there is a genetic mutation Not accepted. Compared to normal Cu / Zn SOD, the H46R mutation has a different copper ion fraction and is a good model for considering the role of copper ions involved in neurodegeneration. Furthermore, clinically, those who have an H46R mutation have a characteristic that the disease duration is very long (Non-patent Document 1), so new Tg mice that have already introduced this mutation have been characterized. Has been made. The ability to create two Tg mice with different promoters so far is one that strongly expresses Cu / Zn SOD throughout the body. Patent Document 2) was used, and the other used the promoter of human Cu / ZnSOD as in the existing Tg mouse for the purpose of comparison with the existing Tg mouse. In previous studies, newly created human H46R mutation-introduced Tg mice have been struggling to cause motor-euron injury in strains in which Cu / Zn SOD is highly expressed in the spinal cord.

[0007] Further, according to Patent Document 1, a novel transgene rat, “Amyotrophic lateral sclerosis (ALS) or a substantially equivalent symptom, is useful as an ALS animal model for the search for anti-ALS drugs. Transgenic rats or their progeny characterized by being capable of being used and methods of use thereof are provided. By using the transgenic rat of the invention, it is possible to efficiently search for a therapeutic drug for ALS disease and confirm the effect. In addition, the ALS model rats of the invention, for example, Tg rats introduced with the human mutant Cu / Zn SOD gene, reproduce the pathology of human ALS well in their symptoms and pathology, and future pathological conditions as ALS model animals. Useful for elucidation and development of treatments.

[0008] Patent Document 1: JP 2002-142610 A

Non-patent literature l: Nat. Genet., 5, 323-324 (1993)

Non-Patent Document 2: J, Gene, 108, 193-199 (1991)

Disclosure of the invention

Problems to be solved by the invention

[0009] An object of the present invention is to provide a pharmaceutical product or a food for specified health use that contains D-allose as an active ingredient and delays the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis. To do. In addition, the present invention provides a subject with a therapeutically effective amount of D-allose to cause the development of movement disorders associated with amyotrophic lateral sclerosis in the subject. The object is to provide a method of delaying symptoms or progression.

[0010] The present invention supplements the prevention and treatment of existing drugs and Z or symptom progression-suppressing effects that have been used conventionally in delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis. And Z or enhance, improve pharmacokinetics, absorption, or dose of the drug 'reducing side effects, and even preventing the development of drug resistance, associated with amyotrophic lateral sclerosis The purpose is to provide a medicine or food for specified health use that delays the onset or progression of movement disorders.

Means for solving the problem

[0011] The gist of the present invention is the following agents (1) to (3) for the onset or progression retardation of movement disorders associated with amyotrophic lateral sclerosis.

(1) An agent for delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis, comprising D-allose as an active ingredient.

(2) Presence of genetic mutations that are positively correlated with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis at risk of suffering from a positive family history of amyotrophic lateral sclerosis Diagnosed as amyotrophic lateral sclerosis at risk of suffering, amyotrophic lateral sclerosis at risk of suffering from environmental exposure, or amyotrophic lateral sclerosis The onset or progression retarding agent according to (1), which delays the onset or progression of movement disorders associated with lateral sclerosis.

(3) Genes that encode a superoxide dismutase gene mutation in amyotrophic lateral sclerosis that has a risk of being affected by the presence of a gene mutation that is positively correlated with amyotrophic lateral sclerosis The onset or progression delaying agent according to (2),

[0012] The gist of the present invention is the following compositions (4) and (5).

(4) A composition in the form of a food or drink or a pharmaceutical comprising the onset or progression retarder of (1), (2) or (3).

(5) Effective amount strength D-allose strength S The composition according to (4), which is 0.5 to 50 g per day.

[0013] The gist of the present invention is the following food and drink (6) to (11).

(6) Containing D-allose as an active ingredient, movement disorders associated with amyotrophic lateral sclerosis Food and drink with an indication that it is used to delay the onset or progression of

(7) Presence of gene mutations that are positively correlated with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis at risk of suffering from a positive family history of amyotrophic lateral sclerosis Diagnosed as amyotrophic lateral sclerosis at risk of suffering, amyotrophic lateral sclerosis at risk of suffering from environmental exposure, or amyotrophic lateral sclerosis The food or drink according to (6), which is used for delaying the onset or progression of movement disorders associated with lateral sclerosis.

(8) A gene that encodes superoxide dismutase due to the presence of a gene mutation that has a positive correlation with amyotrophic lateral sclerosis. The food or drink according to (7), which is present in

(9) The food or drink according to (6), (7) or (8), which is a supplement, functional food, health food, food for specified health use, dietary supplement food or food for the sick.

(10) The food or drink according to (6), (7), (8) or (9), which is in the form of a tablet, round, capsule, powder, granule, fine granule, troche or liquid.

(11) The effective food strength The food or drink according to any one of (6) to (10), wherein the amount of D-allose is 0.5 to 50 g per day.

The gist of the present invention is a method for delaying the onset of movement disorders of the following (12) to (15).

(12) A method of delaying the onset of movement disorder associated with amyotrophic lateral sclerosis in a human subject, comprising administering or feeding an effective amount of D-allose to the subject .

(13) Presence of genetic mutations that are positively correlated with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis at risk of suffering from a positive family history of amyotrophic lateral sclerosis This is a method to delay the onset of amyotrophic lateral sclerosis at risk of suffering or the movement disorder associated with amyotrophic lateral sclerosis at risk of suffering due to environmental exposure (12) The method described in 1.

(14) Due to the presence of a genetic mutation that is positively correlated with amyotrophic lateral sclerosis, (13) The method according to (13), wherein the gene mutation of amyotrophic lateral sclerosis having a risk is present in a gene encoding superoxide dismutase.

(15) The method according to (12), (13) or (14), wherein the amount of D-alose administered or fed is 0.5 to 50 g per day.

[0015] Further, the gist of the present invention is the following (16) and (17) luck treatment methods.

(16) A method of treating a human subject diagnosed with amyotrophic lateral sclerosis, wherein the subject is administered an amount of D-allose effective to delay the progression of motor impairment or Said method comprising feeding.

(17) The method according to (16), wherein the amount of D-allose administered or fed is 0.5 to 50 g per day.

The invention's effect

[0016] The present invention can provide a pharmaceutical product or food for specified health use that contains D-allose as an active ingredient and delays the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis. The present invention also provides a method of delaying the onset or progression of a movement disorder associated with amyotrophic lateral sclerosis in a subject by administering to the subject a therapeutically effective amount of D-allose. I can do it.

The present invention supplements and prevents Z or symptom progression-suppressing effects of conventionally used drugs in delaying the onset or progression of movement disorders associated with amyotrophic lateral sclerosis. Motor disorders associated with amyotrophic lateral sclerosis have the effect of enhancing, improving pharmacokinetics, absorption, or reducing the side effects of the drug and preventing the development of drug resistance Drugs or foods for specified health use that can delay the onset or progression of can be provided.

Brief Description of Drawings

FIG. 1 is a graph showing glutamate release and the effect of D-allose during ischemia using H46R spinal cord slices. The left side of the figure is untreated, and the right side of the figure is brown when the glutamic acid liberated with D-allose is brown.

FIG. 2 is a graph showing the release of hydrogen peroxide and the effect of D-allose on reperfusion using H46R spinal cord slices. The figure on the left is untreated, the figure on the right is D-allose administration belongs to. The liberated hydrogen peroxide is brown.

BEST MODE FOR CARRYING OUT THE INVENTION

[0018] D-Alose (D-A mouth hexose) is a D-form of aroose classified as aldose (Aldo hexose), and is a hexose sugar (C6H1206) with a melting point of 178 ° C. . In the present invention, “D-allose” is a term meaning D-allose and Z or a derivative thereof. D-Alose derivatives will be described. A compound obtained by converting the molecular structure of a starting compound by a chemical reaction is called a derivative of the starting compound. Derivatives of hexose containing D-psicose include sugar alcohols (when monosaccharides are reduced, aldehyde groups and ketone groups become alcohol groups, resulting in the same number of polyhydric alcohols as carbon atoms) and uronic acid (simple Oxidized saccharide alcohol group, naturally known as D-glucuronic acid, galacturonic acid and mannuronic acid), amino sugar (substituted with OH group SNH2 group of sugar molecule, darcosamine, The same applies to derivatives of force D-allose, which are common, such as chondrosamine and glycosides, but are not limited to them! /.

[0019] As a method for producing this D-malose, there is a method in which Rataton D-gallate is reduced with sodium amalgam, or D-psicose is isomerized using L-rhamnose isomerase, and the mixture power is also determined. It can be produced by separating D-allose. As described in JP-A-2004-29106, it is possible to mass-produce a rare sugar D-alose from D-psicose using L-rhamnose isomerase (L-Rhl). In order to produce a mixture of D-allose and D-psicose, it is advantageous to prepare a mixture of D-psicose and D-allose by reacting L-rhamnose isomerase with D-psicose and causing an isomerization reaction. Can be implemented. It can be obtained as a mixed crystal without separating D-psicose and D-allose. Even though the proportion of D-rose in the solution before crystallization is 50% or less than that of D-psicose, the crystal has an equal amount of D-alose or a higher proportion than D-psicose. On the other hand, when D-psicose and D-allose are mixed at a ratio of 1: 1, the composition ratio of the crystals is about 2: 3, and the crystals contain a large amount of D-allose. In other words, when the mixed sugar of D-psicose and D-allose crystallizes, the ratio of D-psicose to D-allose may become a stable crystal structure between about 1: 1 and 2: 3. (PCT / JP2006 / 304151) _o [0020] The present invention relates to an agent for the onset or progression of movement disorders associated with amyotrophic lateral sclerosis, comprising D-allose as an active ingredient, a food or drink or a pharmaceutical containing the progression retarder. A food / beverage product containing D-alose as an active ingredient and labeled to indicate that it is used to delay the onset or progression of movement disorders associated with amyotrophic lateral sclerosis It is about. Therefore, the pharmaceutical product or food for specified health use targeted by the present invention is characterized in that the blended D-rose is contained as an active ingredient.

[0021] Delayed onset or progression of movement disorders associated with amyotrophic lateral sclerosis, including D-allose, together with one or more pharmaceutically acceptable carriers when in pharmaceutical form It is a composition to be made. The pharmaceutical composition comprises a therapeutically effective amount of a pharmacologically active compound of the invention, alone or in combination with one or more pharmaceutically acceptable carriers.

When D-allose is used as the above-mentioned preparation, it can be carried out by a known method. Specifically, for example, it can be carried out as described below.

[0022] The preparation of the present invention comprises tablets, pills, capsules (including node capsules, soft capsules, microcapsules), powders, granules, fine granules, lozenges, sugar coated or coated as necessary. It is preferably used orally as a liquid (including syrups, emulsions and suspensions).

[0023] The preparation of the present invention can be mixed with a physiologically acceptable carrier or the like as long as the effects of the present invention are not inhibited. As physiologically acceptable carriers, various organic or inorganic carrier substances commonly used as formulation materials are used. Excipients, binders, disintegrants, lubricants in solid formulations; solvents in liquid formulations, dissolution Auxiliaries, suspending agents, buffering agents, thickeners, emulsifiers and the like can be mentioned. In addition, preparation additives such as a coloring agent, a sweetening agent, and an anti-acid agent can be used as necessary. Furthermore, the preparation of the present invention may be coated.

[0024] Examples of excipients include lactose, sucrose, D-manntol, D-sorbitol, denpun, pregelatinized starch, dextrin, crystalline cellulose (for example, microcrystalline cellulose), low-substituted hydroxypropyl Cellulose, sodium carboxymethylcellulose, ara Examples include beer gum, dextrin, pullulan, light anhydrous caustic acid, synthetic aluminum silicate and magnesium aluminate metasilicate. Examples of the binder include pregelatinized starch sucrose, gelatin, macrogol, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mann-tonole, trenorose, dextrin, punoreran. , Hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polybulurpyrrolidone (PVP) and the like. Disintegrants include, for example, lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, cross-linked polybutylpyrrolidone, carmellose sodium, croscarmellose sodium, carboxymethylstarch sodium, light anhydrous key acid, low substituted hydroxy Examples include propylcellulose, cation exchanged rosin, partially pregelatinized starch, and corn starch. Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, waxes, colloidal silica, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and aerosil.

Solvents include, for example, water for injection, physiological saline, Ringer's solution, alcohol, polypropylene glycol, polyethylene glycol, medium chain triglyceride (MCT), vegetable oil (eg safflower oil, sesame oil, corn oil, olive oil, cottonseed oil And soy lecithin). Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, Examples thereof include sodium acetate. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Hydrophilic polymers such as alcohol, polybulyl pyrrolidone, carboxymethylenosulellose sodium, methinoresenorelose, hydroxymethinolesellose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, etc. can give. Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate, and the like. As a thickener Examples thereof include natural gums and cellulose derivatives. Examples of the emulsifier include fatty acid esters (eg, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester), wax (eg, beeswax, rapeseed hydrogenated oil, safflower hydrogenated oil). , Palm hydrogenated oil, sitosterol, stigmasterol, campesterol, brush casterol, cacao butter powder, carnauba wax, rice wax, molasses, paraffin, etc.), lecithin (eg, egg yolk lecithin, soybean lecithin, etc.).

[0026] Examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, and water-insoluble lakes). Examples include pigments (eg, aluminum salts of the above-mentioned water-soluble edible tar pigments), natural pigments (eg, j8-branch chin, chlorophyll, bengara, etc.) Sweeteners include, for example, sucrose, lactose, Examples include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, etc. Examples of the antioxidant include sulfite, ascorbic acid and their alkali metal salts, alkaline earth metal salts, and the like.

[0027] For tablets, granules, fine granules, etc., coating is carried out in a usual manner using a coating substrate for the purpose of masking taste, improving light stability, improving appearance or enteric properties, etc. May be. Examples of the coating base include sugar coating base, water-soluble film coating substrate, enteric film coating substrate and the like.

[0028] Examples of the sugar coating base include sucrose, and one or more kinds of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnaparou and the like can be selected.

[0029] Examples of water-soluble film coating bases include, for example, senorelose such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethylcellulose, hydroxy chineno sesenorelose, and methino les hydroxy ethino reseno llellose. Polymers; Polyvinylacetal Jetylamino Acetate, Aminoalkyl Meta Atrylate Copolymer E (Eudragit E (trade name), Rohm Farma) Polyburyl Pyrrolidone, etc. Synthetic polymers; Polysaccharides such as pullulan . Examples of enteric film coating bases include hydroxypropylmethylcellulose phthalate and hydroxypropylmethacrylate. Cellulose polymers such as chilled cellulose acetate succinate, carboxymethylethyl cellulose, and cellulose acetate phthalate; methacrylic acid copolymer L (Eudragit L (trade name) Rohmfarma), methacrylic acid copolymer LD (Eudragit L— 30D 55 (trade name) ROHM FALMA Co., Ltd.) Acrylic polymers such as methacrylic acid copolymer S (Eudragit S (trade name) KOH FARMA Co.); natural products such as shellac These coating bases may be coated singly or in combination of two or more at an appropriate ratio, or two or more may be sequentially coated.

[0030] When the composition is in the form of a food or drink, or there is a food or drink with an indication of function or efficacy, the food composition or food or drink of the present invention is a functional food, health food, It is preferably prepared as a functional food that may be prepared as a food for specified health use, a food for the sick, a supplement or the like. Examples of the shape of the food composition or food / beverage product of the present invention include tablets, rounds, capsules (including node capsules, soft capsules, and microcapsules), powders, granules, fine granules, and troches. And liquid (including syrup, milk, and suspension), and tablet-like and capsule-like are preferred.

[0031] The food composition of the present invention is particularly preferably in the form of tablets and capsules. In particular, functional foods in the form of tablets and functional foods in the form of capsules are preferred.

[0032] The food composition of the present invention can be produced, for example, by incorporating D-allose in food by a known method. Specifically, for example, a tablet-shaped food composition includes, for example, D-allose and raw materials such as excipients (for example, lactose, sucrose, mannitol, etc.), sweeteners, and flavoring agents. Can be produced by adding and mixing them, and forming pressure into the tablet with a tableting machine. If necessary, other materials (for example, vitamins such as vitamin C, minerals such as iron, dietary fiber, etc.) can be added. Capsule-shaped food compositions are filled with capsules with a liquid, suspension, paste, powder, or granular food composition containing D-allose, or encapsulated with a capsule base, for example. Can be manufactured.

[0033] In the food composition of the present invention, as long as the effects of the present invention are not impaired, commonly used food materials, food additives, various nutrients, vitamins, and flavor substances (for example, cheese and chocolate) In addition, a physiologically acceptable carrier and the like can be blended. Menstruation As the pharmaceutically acceptable carrier, various conventional organic or inorganic carrier materials are used, and excipients, binders, disintegrants, lubricants, coloring agents, sweeteners, preservatives, antioxidants, Examples include thickeners and emulsifiers. Examples of food additives include coloring agents, sweetening agents, preservatives, antioxidants, and flavoring agents. Furthermore, other materials, for example, minerals such as iron, dietary fibers such as pectin, carrageenan and mannan may be contained.

[0034] As an excipient, a binder, a disintegrant, a lubricant, a solvent, a solubilizing agent, a suspending agent, a buffer, a thickener, a coloring agent, a sweetening agent, an antiseptic, and an antioxidant, Examples thereof are the same as those used in the preparation of the present invention described above.

[0035] The vitamins may be water-soluble or fat-soluble, for example, retinol palmitate, tocopherol, bisbenchamine, riboflavin, pyridoxine hydrochloride, cyanoconoramine, sodium ascorbate, cholecalcifer. Rolls, nicotinic acid amide, calcium pantothenate, folic acid, piotin, choline bitartrate and the like.

[0036] With regard to tablet-like, granule-like, fine-grained food compositions, etc., they are known per se using coating substrates for the purpose of masking taste, improving light stability, improving appearance, or enteric properties. You may coat by the method. Examples of the coating substrate include those similar to those used in the above-mentioned preparation of the present invention, and can be carried out in the same manner.

[0037] In the present invention, because D-allose is safe, it can be administered to any ordinary person and Z or fed as a preventive measure against the possibility that an individual may develop ALS in the future. Good. In a preferred embodiment of the present invention, D-alose is administered to individuals suspected of being at risk for ALS and examples of causes that may be at risk of being administered or Z or feeding include higher than normal incidence of ALS. There are certain genetic trends as a result of mutations in a family member with a rate or, for example, in the SOD gene. In a preferred embodiment of the present invention, another category of subjects that may be treated prophylactically with D-allose includes environmental exposures (eg, pesticides, herbicides, organic solvents, Those who have been exposed to mercury, lead, manganese, or selenium), smokers or those who have trauma to the nervous system.

[0038] Furthermore, D-allose is preferably used in subjects at an early stage of ALS, preferably diagnosed with ALS. It may be administered after receiving a judgment that it is correct. For purposes of definition, the period considered “early stage” is one year from the onset of symptoms.

[0039] In a further embodiment, D-allose is used to delay the onset of symptoms (especially the motor system), for example to delay vocal disturbances, and breathing associated with Z or cranial motor nerve dysfunction It may be administered in later stages of ALS to delay muscular damage. For definition, patients with ALS for more than a year are at a later stage of the disease.

[0040] When humans ingest D-allose and Z or their derivatives, the dosage should be determined by the individual's age, weight and symptoms, etc. In many cases, effective doses are D-allose and Z Or, when the derivative is used, it is appropriate to take 0.01-100 g per day, preferably 0.5-50 g, and take it before meals, after meals or with meals.

[0041] In a preferred embodiment of the present invention, D-allose is administered orally and Z or fed, but includes subcutaneous, inhalation, intravenous, subarachnoid, rectal, or any other suitable route of administration. Other routes of administration can also be utilized. Formulations containing D-alose can vary using standard techniques and compounds, depending on the mode of administration.

[0042] Details of the present invention will be described in Examples. The present invention is not limited by these examples.

Example

[0043] Although there are many unclear parts regarding the pathology of ALS, at least in familial ALS, the overproduction of reactive oxygen species due to the point mutation of SOD and the processing failure are striking.

The generation of reactive oxygen species is a type of neurotransmitter, but it is thought to be due to glutamic acid that exhibits strong neurotoxicity when secreted in large quantities.

It is well known that reactive oxygen species are produced from buds, sugars, and oxygen in the case of glutamate toxicity.

The present inventors have already clarified that D-alulose suppresses the production of active oxygen during cerebral ischemia / reperfusion and prevents delayed neuronal cell death (WO2003Z097820) [0044] Then, we examined the effect of D-allose on the ALS model. [experimental method]

1. Transgenic mice use seeds distributed by the Department of Neurology, Tohoku University, and continue to cross at the Kagawa University Animal Laboratory to preserve the species!

2. A 5mm portion of the H46R mouse tail was cut and dissolved in the lysate, and then the DNA was extracted. Using this DNA, PCR was performed and it was confirmed whether the target gene was introduced.

3. Since paralysis of H46R mice occurs from around 130 days, 2 g / kg of D-rose dissolved in physiological saline at 9 am was orally administered once a day at 9 am from 100 days after birth. In the control group, glucose dissolved in physiological saline was orally administered in the same manner at 2 g / kg.

4. Behavior was analyzed using visual observation and a motion analysis device (rotating cage motion measurement device). At the same time, video was recorded.

5. As part of the mechanism of action analysis, glutamate release experiments from the spinal cord were performed. Slices were made using an 80-day-old H46R spinal cord, an acrylic self-made chamber was placed under the microscope, and the release of glutamate during ischemia 'reperfusion was observed in the presence and absence of D-allose. did.

[0045] [Experimental results]

1. Therapeutic effect of A-Dose on ALS

The average life span of H46R mice is 163 ± 16.4 days, whereas in the D-alose group, survival is significantly prolonged at 189 days ± 8.0 days. This mouse develops at 151 ± 16.8 days, progresses from both lower limb paralysis to both sides, further into the upper limb, and eventually dies due to respiratory muscle paralysis. Susceptibility The number of days until death is 12.3 ± 2.6 days. During this time, the progression of paralysis is continuous, and the pathology progresses such as paralysis, progress, and stiffness of the lower limbs. On the other hand, in the D-rose group, the period until onset is 160.0 ± 6.8 days, and the onset tends to be delayed. Furthermore, the onset of death in the D-allose administration group is 30.8 ± 4.8 days, and the period from onset to death in the non-administration group is significantly extended. This is thought to be due to a delay in the progression of each symptom. The results for ALS of D-Alose are shown in Table 1.

[0046] [Table 1] Effects of D-Alloys on ALS mice

[0047] These results are almost as effective at the experimental animal level as riluzole, which is currently the only approved treatment for ALS. In addition, it has the same effect as the recently reported gene therapy of insulin-like growth factor, and it is surprising that the same effect was observed in the monosaccharide D-allose.

[0048] 2. Analysis of the effect and mechanism of action of D-allose on ALS

As part of the work mechanism analysis, glutamate release experiments from the spinal cord were performed. D-Allose inhibits the release of glutamate, which has neurotoxicity in ischemia and reperfusion (Fig. 1). Glutamic acid is specifically released to gray matter and turns brown in this method. The right side of Fig. 1 shows release in the presence of D-alose, but it is significantly suppressed. The effect was almost the same as rilzole. In addition, 2-deoxyglucose, an antimetabolite of glucose, showed similar effects.

Furthermore, it suppresses the generation of hydrogen peroxide (Η 0) that is liberated during recirculation and has neurotoxicity.

twenty two

(Fig. 2). Hydrogen peroxide is specifically liberated in gray matter and turns brown in this method. The right side of Fig. 2 shows the release in the presence of D-alose, which is significantly suppressed.

In this way, the mechanism of action of D-allose has been elucidated specifically, such as the suppression of glutamate release and the suppression of hydrogen peroxide production! /

[0049] [Conclusion]

1. It has been clarified that D-allose has a life-prolonging effect by delaying the onset of familial ALS model mice H46R and significantly delaying the progression.

2. As one of the mechanism of action, it became clear that the release of glutamate, which has motor neurotoxicity, was suppressed.

3. In addition, as a second mechanism of action, peroxy 匕, a reactive oxygen species that has motor neurotoxicity It became clear that suppressing the production of hydrogen.

4. From the above, it is considered that D-alulose is effective for ALS by inhibiting both the release of glutamic acid and the generation of reactive oxygen species, thereby inhibiting the death of motor neurons in the spinal cord.

Industrial applicability

The present invention provides a method for delaying the onset or progression of a movement disorder associated with ALS in a subject comprising administering to the subject a therapeutically effective amount of D-allose. This is based, at least in part, on the finding that D-allose was able to delay the onset of movement disorders in H46R-mutated Cu / ZnSOD gene-introduced ALS model mice. Thus, D-allose prophylactically treats the general population and more specifically individuals who are considered at risk of developing ALS (for example, because of a positive family history of the disease and the presence of a Z or genetic defect) Can be used for. In addition, D-allose delays the progression of preexisting movement disorders and to delay the onset of movement disorders in the motor system, which is Z or still susceptible to the disease. Can be used to treat individuals who have already been diagnosed with ALS. A great impact and demand can be expected for these medicines or special health foods.

Claims

The scope of the claims

[1] An agent for delaying the onset or progression of movement disorder associated with amyotrophic lateral sclerosis, comprising D-allose as an active ingredient.

[2] Due to a positive family history of amyotrophic lateral sclerosis, the presence of genetic mutations that are positively correlated with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis at risk of suffering Is diagnosed as amyotrophic lateral sclerosis at risk of suffering, amyotrophic lateral sclerosis at risk of suffering due to environmental exposure, or amyotrophic lateral sclerosis The onset or progression retarding agent according to claim 1, which delays the onset or progression of movement disorders associated with lateral sclerosis.

[3] Due to the presence of a gene mutation that is positively correlated with amyotrophic lateral sclerosis, the gene mutation of the amyotrophic lateral sclerosis that is at risk of suffering from a gene that encodes superoxide dismutase The onset or progression delaying agent according to claim 2, which is present.

[4] A composition in the form of a food or drink or a medicine containing the onset or progression retarding agent according to claim 1, 2 or 3.

[5] The composition according to claim 4, wherein the effective amount is 0.5 to 50 g per day of the amount of D-allose.

[6] A food or drink product that contains D-allose as an active ingredient and is labeled as being used to delay the onset or progression of movement disorders associated with amyotrophic lateral sclerosis.

[7] Presence of genetic mutations that are positively correlated with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis at risk of suffering from a positive family history of amyotrophic lateral sclerosis Is diagnosed as amyotrophic lateral sclerosis at risk of suffering, amyotrophic lateral sclerosis at risk of suffering due to environmental exposure, or amyotrophic lateral sclerosis The food or drink according to claim 6, which is used to delay the onset or progression of movement disorders associated with lateral sclerosis.

[8] Due to the presence of a gene mutation that is positively correlated with amyotrophic lateral sclerosis, the gene mutation of amyotrophic lateral sclerosis that is at risk of suffering from the gene encoding superoxide dismutase The food / beverage product of Claim 7 which exists.

[9] supplements, functional foods, health foods, foods for specified health use, dietary supplements or diseases The food or drink according to claim 6, 7 or 8, which is a food for consumers.

[10] The food or drink according to claim 6, 7, 8, or 9, which is in the form of a tablet, round, capsule, powder, granule, fine granule, troche or liquid.

[11] The food or drink according to any one of claims 6 to 10, wherein the effective amount is 0.5 to 50 g per day.

[12] A method for delaying the onset of a movement disorder associated with amyotrophic lateral sclerosis in a human subject, comprising administering or feeding an effective amount of D-allose to the subject.

[13] Presence of genetic mutations positively correlated with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis at risk of suffering from a positive family history of amyotrophic lateral sclerosis Is a method of delaying the onset of amyotrophic lateral sclerosis at risk of suffering or movement disorders associated with amyotrophic lateral sclerosis at risk of suffering due to environmental exposure Item 13. The method according to Item 12.

[14] Gene mutation that positively correlates with amyotrophic lateral sclerosis, due to the presence of a gene mutation, the gene mutation ability of amyotrophic lateral sclerosis that is at risk of suffering 14. A method according to claim 13 present.

[15] The amount of D-allose administered or fed is between 0.5 and 50 g per day.

The method according to 13 or 14.

[16] A method of treating a human subject diagnosed with amyotrophic lateral sclerosis, wherein the subject is administered or fed an amount of D-allose effective to delay the progression of motor impairment. Said method comprising eating.

[17] The method according to claim 16, wherein the amount of D-allose administered or fed is 0.5 to 50 g per day.